Activation of mitochondrial fusion provides a new treatment for mitochondria-related diseases

Biochem Pharmacol. 2018 Apr;150:86-96. doi: 10.1016/j.bcp.2018.01.038. Epub 2018 Feb 3.


Mitochondria fragmentation destabilizes mitochondrial membranes, promotes oxidative stress and facilitates cell death, thereby contributing to the development and the progression of several mitochondria-related diseases. Accordingly, compounds that reverse mitochondrial fragmentation could have therapeutic potential in treating such diseases. BGP-15, a hydroxylamine derivative, prevents insulin resistance in humans and protects against several oxidative stress-related diseases in animal models. Here we show that BGP-15 promotes mitochondrial fusion by activating optic atrophy 1 (OPA1), a GTPase dynamin protein that assist fusion of the inner mitochondrial membranes. Suppression of Mfn1, Mfn2 or OPA1 prevents BGP-15-induced mitochondrial fusion. BGP-15 activates Akt, S6K, mTOR, ERK1/2 and AS160, and reduces JNK phosphorylation which can contribute to its protective effects. Furthermore, BGP-15 protects lung structure, activates mitochondrial fusion, and stabilizes cristae membranes in vivo determined by electron microscopy in a model of pulmonary arterial hypertension. These data provide the first evidence that a drug promoting mitochondrial fusion in in vitro and in vivo systems can reduce or prevent the progression of mitochondria-related disorders.

Keywords: BGP-15; Mitochondrial fragmentation; Optic atrophy 1; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • HeLa Cells
  • Humans
  • Male
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondrial Diseases / drug therapy*
  • Mitochondrial Diseases / metabolism*
  • Mitochondrial Diseases / pathology
  • Mitochondrial Dynamics / drug effects
  • Mitochondrial Dynamics / physiology*
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Oximes / pharmacology
  • Oximes / therapeutic use*
  • Piperidines / pharmacology
  • Piperidines / therapeutic use*
  • Rats
  • Rats, Wistar
  • Treatment Outcome


  • Enzyme Inhibitors
  • Oximes
  • Piperidines
  • BGP 15